Rapid detection of the release of weaponized pathogens is critical for public defense against bioterrorist attacks. Continuous surveillance against surprise releases is difficult, particularly in large or remote areas. We propose to develop mouse strains that are genetically hypersensitive to the presence of bioterrorist pathogens and that would exhibit anaphylactic shock and rapid death when exposed to bioweapon organisms. The overall goal is to produce animals that would have dramatic and rapid physiological responses to pathogens and serve as sentinels for pathogen release. The aims of this proposal are directed toward preliminary studies to explore the feasibility of this approach. Although the approach can easily be directed toward most pathogens, these preliminary studies will use Bacillus anthracis as a model bioterrorist organism. One (1) specific aim is to produce mouse strains that carry antibody heavy and light chain transgenes encoding IgE antibodies specific for the BclA protein that is the immunodominant epitope on the exosporium of B. anthracis. These mice (Ax-IgE mice) are designed to have highly elevated anti-anthrax IgE levels that will cause them to have allergic hypersensitivity to exposure to anthrax spores. The remaining aims are to further genetically modify Ax-IgE mice to increase their sensitivity to anthrax. This will be done by crossing the Ax-IgE mice with mice that are deficient for inhibitory factors that have been shown to downregulate allergic reactions. The short-term R21 support will allow these preliminary studies to show the specificity and sensitivity of these genetically modified mice to exposure to anthrax spores. This will indicate the potential effectiveness of this new approach to pathogen surveillance and provide a basis for a series of future studies to expand and refine this technology.